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14 mitochondrial hepatopathy ahmedabad-july-2012

14 mitochondrial hepatopathy ahmedabad-july-2012






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    14 mitochondrial hepatopathy ahmedabad-july-2012 14 mitochondrial hepatopathy ahmedabad-july-2012 Presentation Transcript

    • Mitochondrial Cytopathy Prof. Surender K Yachha Department of Pediatric Gastroenterology SGPGIMS, Lucknow
    • Mitochondria: “Powerhouse” of the cell FAOD RCD
    • Defect
    • Mitochondrial diseases High energy dependency In disease Mutant mitochondrial DNA >>> normal DNA and consequentially shifting proportions Shift from one clinical phenotype to another with age
    • Mitochondria and respiratory chain Dependence on Aerobic pathway for ATP Anaerobic pathway(oxidative phosphorylation) (glycolysis) Increase lactate 38 ATP Only 2 ATP
    • 80% calories (during fasting) 24 hr: adults 12 hr: infants Most affected
    • ConsequencesGlycolysis Hypoglycemia Not metabolised Respiratory Try to spare in FAOD chain defects glucose
    • Disorders inMitochondrial Hepatopathy1. Fatty Acid Oxidation Defects 2. Respiratory Chain Defects
    • “The Masquerader Of All Diseases” Highly Deceptive !
    • Why do we struggleto identify this disease ? Mitochondrial Diseases
    • Settings to predict this disease
    • Settings in GI practice
    • 107 patients FAOD 74% 30% 31% 13% 16% 10%<1mo 1mo – 1yr 1yr – 2 yr >2yr unknown 36% 40% 8% 12% 0.01% 82% N= 50 Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
    • 24%8% FAOD & RCD - Clinical features8%3%8%8%20% Lee ,Sokol Semin Liver Dis5% 2007;27:259–273.
    • Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
    • FAOD ImportanceShort Chain  Not much of a problemDoes it really exist??  Developmental delay  Behavioural problemsMedium Chain (80%)  Good prognosis(1:15,000 new born screen)  Maximum heterogeneity  Mortality: 16-25%  Intellectual delay 20-25%  <6yr : decompensation  >6yr : death risk reducedLong Chain  Mainly liver manifestations(1:85,000 new born screen)  Adverse prognosisPrimary Carnitine deficiency  Early presentation and death(1:750,000 - 2,000,000) J Inherit Metab Dis (2010) 33:501–506
    • Long Chain Hydroxy Acyl CoA Dehydrogenase Def. (LCHADD) Early onset: severe Hypertrophic cardiomyopathy phenotype Pericardial effusion Lethality 40-80% May have HE Neonatal CholestasisInfantile onset: hepatic Hepatomegaly, steatosis phenotype (steatosis) HypoglycemiaLate onset: myopathic Exercise induced rhabdomyolysis phenotype (CK: 200,000 u/l: acute 500-5000 u/l
    • Very Long and Long ChainHydroxy Acyl CoA Dehydrogenase Def. (VLCHADD and LCHADD) J Inherit Metab Dis (2010) 33:501–506
    • Biochemical differentiation Acidosis Urine Blood sugar Serum Serum ketones Lactate AmmoniaFAOD ++ Nil Low + + (non-ketotic hypoglycemia)RCD ++ ++ Normal ++++ ±OA +++ ++/+++ Low/ Normal/ Normal ++ (persistent) HighUCD Normal ++++
    • Fatty Acid Oxidation Defects Screening Definitive (available in India) (NOT available) Tandem MS: Quantitative Fatty acid analysis C8-10 in MCAD C14-18 in LCHAD Enzyme activity in C14 in VLCAD cultured skin fibroblasts or muscle + Plasma carnitine and acylcarnitine assay biopsy •Very low levels reaching zero: Carnitine def. also primary carnitine def •25-50% reduction: Other FAODGCMS: Urinary organic acid and acylglycine assay (available) - dicarboxyllic acids
    • Respiratory Chain Defects involving Liver Disorder Onset Disorder OnsetNeonatal Liver Acute Pearsons synd Insidious failure Villous atrophy syndrome ChronicMitochondrial AcuteDNA depletion Navajo Acute / Alpers synd Insidious Neurohepatopathy chronic
    • Respiratory Chain Defects involving LiverNeonate Infancy Childhood Adult
    • Respiratory Chain Defects
    • Definitive Sample Availability Tests in India Ragged red fiber Muscle Yes (Histology) Analysis of oxygen Liver, muscles, fibroblasts Noconsumption Polarographic fresh biopsy specimens studies required (5-10gm) Enzymatic activity of Frozen samples No respiratory chain (liver, kidney, myocardium) complexes larger tissue (open surgical in most centers) Mt DNA deletions and Muscle No mutations
    • Treatment Lee ,Sokol Semin Liver Dis 2007;27:259–273
    • Role of Carnitine Lee ,Sokol Semin Liver Dis 2007;27:259–273